A genetic model for control of RNA polymerase II function by Ess1-mediated isomerization of the C-terminal domain (CTD).
Steven
D. Hanes, Xiaoyun Wu, Cathy B. Wilcox, Gina Devasahayam, Vishnu
Chaturvedi
Dept. of Biomedical Sciences, Wadsworth Center/SUNY-Albany, 120 New Scotland Ave, Albany, NY 12208, USA
Ess1, is an
essential prolyl-isomerase in S. cerevisiae that is conserved
from yeast to humans. Ess1 recognizes phospho-Ser-Pro motifs and binds
to the CTD of Rpb1, the large subunit of RNA pol II. The CTD consists of
26 YSPTSPS repeats, and is thought to act as a landing-pad for protein
complexes (e.g. initiation, elongation, termination, 3' end
formation, splicing) required for ordered transcription. A major
question is how the binding of these complexes is coordinated in a
stepwise fashion. The CTD undergoes reversible phosphorylation. This is
one mechanism by which protein binding might be regulated. A second
mechanism might also be important; conformational isomerization of the
CTD by Ess1. Consistent with such a model, we showed physical and
genetic interactions between Ess1 and Rpb1, and identified high-copy
suppressors of ess1-ts mutants that include RNA pol II subunits
and cofactors. Ess1 acts positively on RNA pol II, opposing the action
of the Rsp5 ubiquitin-ligase, which also binds the CTD. ESS1
also shows genetic interactions with genes encoding 3 CTD kinases,
KIN28, CTK1 and SRB10. The interactions suggest
that Ess1 acts at multiple steps in transcription, stimulating PIC
formation and promoter release, and later blocking elongation, allowing
termination and 3' end formation to occur. Finally, ESS1 was
cloned from C. albicans and shown to be essential for growth and
morphogenetic switching, suggesting that it might be a useful antifungal
drug target.
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